Diabetes mellitus is a condition in which the body either does not produce enough, or does not properly respond to, insulin, a hormone produced in the pancreas. There are 2 main types of diabetes. Type 1 diabetes is when the body does not produce insulin, of which only 5-10% of people with diabetes have Type 1 diabetes. 23.6 million children and adults in the United States have Type 2 diabetes (T2D; www.diabetes.org). In T2D, either the body does not produce enough insulin or cells in the body do not response to insulin resulting in high levels of sugar in the blood. Pregnant women who have never had diabetes before but who have high blood glucose levels during pregnancy are said to have gestational diabetes. Gestational diabetes affects about 4% of all pregnant women and may precede development of T2D. Studies have shown that an increase in abdominal fat is associated with glucose intolerance. A body mass index of over 40 has been linked to a higher chance of developing diabetes. T2D and obesity are major public health priorities because of their high prevalence and incidence nationwide and their long-term health implications. The complete citation for the references cited are provided hereinbelow.
The underlying pathophysiology associated with both obesity and diabetes has been linked to the naturally occurring hormone ghrelin. Ghrelin is an acylated 28 amino acid peptide which in 1999 was discovered to be the endogenous ligand of the growth hormone secretagogue receptor (GHS-R; Kojima et al., 1999). The n-octanoyl group at serine 3 of ghrelin is essential for GHS-R binding and function, whereas the unacylated des-acyl ghrelin, does not activate the GHS-R (Kojima et al., 1999; 2001; Boglio et al., 2003b). Ghrelin is predominantly expressed in specialized cells located within the gastric oxyntic mucosa which provides the major source of circulating ghrelin (Date et al., 2000; Ariyasu et al., 2001; Dornonville de la Cour et al., 2001; Rindi et al., 2002). In addition, ghrelin-producing epsilon cells have been identified in the developing and adult human pancreas (Wierup et al., 2002; Andralojc et al., 2009) and to a lesser extent in the intestine, kidney, immune system, placenta, testis, pituitary, lung and hypothalamus (Kojima et al., 1999; Hosoda et al., 2000; Date et al., 2000; Mori et al., 2000; Gualillo et al., 2001; Tanaka et al., 2001; Date et al., 2002; Gnanapavan et al., 2002; Hattori et al., 2001; Lu et al., 2002; Mucciolo et al., 2002; Sakata et al., 2002; Tena-Sempere et al., 2002; Volante et al., 2002 a,b; Mondal et al., 2005).
To date, ghrelin is the only identified hunger hormone. The preprandial rise and postprandial fall in plasma ghrelin levels support the hypothesis that ghrelin plays a physiological role in meal initiation in humans (Cummings et al., 2001). The baseline and pulsatile pattern of ghrelin is inhibited in obese subjects following gastric bypass surgery (Cummings et al., 2002; Roth et al., 2008). Endogenous acylated ghrelin has been reported to be elevated in obese T2D (Rodriguez et al., 2009) and these levels have an inverse correlation with insulin sensitivity (Barazzoni et al., 2007). Several human genetic studies have demonstrated an association between ghrelin polymorphisms and body mass index or other obesity-related phenotypes (Chung et al., 2009; Tang et al., 2008; Robitaille et al., 2007; Ando et al., 2007; Korbonits et al., 2002; Ukkola et al., 2002; Kilpelainen et al., 2008). A few studies have also shown a ghrelin variant association with T2D (Mager et al., 2006; Poykko et al., 2003). In addition to ghrelin itself, human genetic data also support the role of the GHS-R in metabolic disease. It has recently been shown that the A/A genotype (rs2922126) in the promoter is linked with metabolic syndrome, increased waist circumference and increased fasting plasma glucose in women. The A/A genotype (rs509030) in the intron was also associated with lower plasma high density lipoprotein in women. These data suggest that polymorphisms within GHS-R might be a genetic risk factor for metabolic syndrome in women (Li et al., 2008).
Deletion of ghrelin in ob/ob mice augments insulin secretion in response to a glucose challenge (Sun et al., 2006). In contrast, an over-expressing ghrelin mouse model has a decreased insulin secretion in response to a glucose challenge (Iwakura et al., 2009). These data supporting the hypothesis that endogenous ghrelin can cause glucose intolerance.
Exogenous ghrelin also increases blood glucose and decreases insulin levels in humans and rodents (Broglio et al., 2001, 2002, 2003a,b; Arosia et al., 2003; Broglio et al., 2004; Sun et al., 2006; Dezaki et al., 2004). The ghrelin-induced hyperglycemia is abolished by the peptide GHS-R antagonist [D-Lys3]-GHRP-6 (Dezaki et al., 2004). In addition, ghrelin infusion in rodents and humans inhibits glucose-stimulated insulin secretion in vivo (Reimer et al., 2003; Dezaki et al., 2007; Tong et al., 2009).
The effects of ghrelin on insulin secretion are directly within the pancreatic islet as many authors have confirmed that the GHS-R is present in islets (Date et al., 2002; Gnanapavan et al., 2002; Volante et al., 2002a; Wierup et al., 2004; Wierup & Sunder, 2005; Kageyama et al. 2005). Exogenous ghrelin also decreases glucose-induced insulin release in rat and mouse islets and in the rat perfused pancreas (Egido et al., 2002; Colombo et al., 2003; Reimer et al., 2003; Dezaki et al., 2004; Dezaki et al., 2006). Dezaki et al. (2004; 2006; 2007; 2008) provided the first evidence to support the hypothesis that endogenous ghrelin in rodent islets acts directly on β-cells to inhibit glucose-induced insulin, as the peptide GHS-R antagonist and a ghrelin anti-serum increased intracellular calcium in response to glucose. In addition, the glucose-induced insulin release from isolated islets of ghrelin knock-out mice is greater than wild type. The inhibitory effects of ghrelin on glucose-induced changes in intracellular calcium is abolished by pertussis toxin, an inhibitor of Gi/o subtypes of GTP binding proteins.
GHS-R peptide antagonists have been reported to reduce fasting blood glucose in mice (Asakawa et al., 2003; Dezaki et al., 2004). More recently, a small molecule non-peptide antagonist has been shown to improve glucose tolerance in rats by stimulating insulin release without hypoglycemia (Elser et al., 2007).
In addition to modulating insulin secretion and glucose tolerance, exogenous ghrelin has been shown to modulate insulin sensitivity. Intravenous infusion of ghrelin in man increases plasma glucose, increases free fatty acids, and reduces glucose disposal rates compatible with an impairment of insulin sensitivity (Gauna et al., 2004; Lucidi et al., 2005; Damjanovic et al., 2006; Vestergaard et al., 2007; 2008a, b).
The effects of ghrelin are mediated via the GHS-R as Longo et al., (2008) have reported loss of the ghrelin receptor in mice improves insulin sensitivity. GHS-R knock-out mice fed a high-fat diet had several measures of greater insulin sensitivity, including: lower fasted blood glucose and plasma insulin, lower % HbA1c, lower insulin levels during glucose tolerance tests, and improved performance in hyperinsulinemic-euglycemic and hyperglycemic clamp studies. The knockout mice fed a high-fat diet also did not develop hepatic steatosis and had lower total cholesterol, relative to controls. Furthermore, the knock-out demonstrated a lower intestinal triglyceride secretion rate of dietary lipid.
It is well established that ghrelin increases food intake in rodents (see Chen et al., 2009). In addition to preclinical data, acute administration of exogenous ghrelin has been shown to stimulate food intake humans (Wren et al., 2001; Druce et al., 2005; Huda et al., 2009). Several lines of evidence support a role for endogenous ghrelin in the control of food intake. Anti-ghrelin antibodies and knockdown of the GHS-R suppress food intake in rats (Nakazato et al., 2001, Shuto et al, 2002). Both ghrelin knockout and GHS-R null mice have been reported by separate groups (Zigman et al., 2005; Wortley et al., 2005). GHS-R null mice were leaner than wild type when fed normal chow and were resistant to high fat diet-induced obesity. Ghrelin knock-out mice also have a reduced Respiratory Quotient, suggesting that ghrelin may act as a nutrient sensor and its absence may promote increased fat utilization.
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